Purpose: To investigating the role of mitochondrial haplotypes in the development of Leber's hereditary optic neuropathy (LHON) associated with the ND4 G11778A mutation in Chinese families.
Methods: A three-generation Chinese family with LHON was studied by clinical and genetic evaluation as well as molecular and biochemical analysis of mitochondrial (mt)DNA.
Results: This family exhibits a high penetrance and expressivity of visual impairment. The average age at onset was 13.9 years in this family. Of the family members, 86% of the male and 29% of the female matrilineal relatives had visual loss, with a wide range of severity, from blindness to nearly normal vision. Molecular analysis of mtDNA identified the homoplasmic ND4 G11778A mutation and 35 other variants, belonging to the Asian haplogroup D5. Of other variants, the novel homoplasmic A4435G mutation absent in 164 Chinese controls is localized at 3' end adjacent to the anticodon, at conventional position 37 (A37), of tRNAMet. The adenine (A37) at this position of tRNAMet is extraordinarily conserved from bacteria to human mitochondria. This modified A37 was shown to contribute to the high fidelity of codon recognition and to the structural formation and stabilization of functional tRNAs. In fact, the significant reduction of the steady state levels in tRNAMet was observed in cells carrying the both the A4435G and G11778A mutations but not cells carrying only the G11778A mutation. Thus, a failure in mitochondrial tRNA metabolism, caused by the A4435G mutation, may worsen the mitochondrial dysfunction associated with the primary G11778A mutation.
Conclusions: The novel tRNAMet A4435G mutation has a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.